Trafficking

By MD FACP Buckingham Robert

Have you ever wondered how we age and why we get sick? Trafficking, the third book in a trilogy that includes Hazing Aging and Rejuvenation!, exposes the chronic inflammatory underworld and how it does its dirty business to transform end organ interstitial spaces into a sea of diseases. The book clarifies how this

• Language: English
• Publisher: LitFire Publishing
• Release date: Dec 18, 2019
• ISBN: 9781641515283

MD FACP Buckingham Robert

I have been a practicing physician in a variety of hospital and clinic settings for 36 years. My experience in critical care, coupled with my work in noninvasive cardiac care, has provided me with unique insight into the origins of inflammation and which cells really matter in the process.The purpose for writing Hazing Aging was to allow everyone the opportunity to see what i was seeing and to make adjustments in their life based on purpose and understanding of cause and effect mechanisms.It is my intention to continue this process of sharing my insights and have written two additional books on capillary endothelia, which will be published in the next 12-16 months.In the meantime, settle in and begin the adventure of making your capillary cells healthy through anti-inflammatory living.

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Trafficking

How Chronic Inflammation Sabotages the Immune Arsenal

and Poisons the Interstitial Space of End Organs

Copyright © 2018 by Robert Buckingham, MD, FACP

All rights reserved. No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the publisher or author, except in the case of brief quotations embodied in critical reviews and certain other noncommercial uses permitted by copyright law.

Although every precaution has been taken to verify the accuracy of the information contained herein, the author and publisher assume no responsibility for any errors or omissions. No liability is assumed for damages that may result from the use of information contained within.

ISBN: 978-1-64151-528-3

Printed in the United States of America

LitFire LLC

1-800-511-9787

www.litfirepublishing.com

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Trafficking

How Chronic Inflammation Sabotages the Immune Arsenal and

Poisons the Interstitial Space of End Organs

Robert Buckingham, MD, FACP

Table of Contents

Introduction

CHAPTER 1

The Parable of the Farmer

CHAPTER 2

The Trap Door to Our Immune System

CHAPTER 3

The Parable of the Old Woman

CHAPTER 4

Lifestyle Choices: Down Shifting Inflammatory Momentum by Reducing Vascular Inflammatory Free Radicals

CHAPTER 5

The Planting and Growth of Chronic Inflammation

CHAPTER 6

Permeability Mechanics of Trafficking

CHAPTER 7

The Consolidation of Chronic Interstitial Space Inflammation

CHAPTER 8

THE PARABLE OF THE SUN, LAND AND SEA

CHAPTER 9

The Bad and Ugly of Chronic Inflammation

CHAPTER 10

The Making of Interstitial Space Sanitation: How Capillary –Endothelial Cell Anatomy Archives Immune Arsenal Trafficking

CHAPTER 11

What Capillary Cells are Trafficking

CHAPTER 12

Trafficking Methods

CHAPTER 13

Parodies to Inflammatory Mediator Trafficking

CHAPTER 14

How to Prevent a Traffic Tie-Up

GLOSSARY OF TERMS

APPENDIX

Graph 1: The Stacking of Vascular Inflammatory Free radicals, Poor Lifestyle Choices and Subsequent Disease Venues on Mortality (Courtesy of Hazing Aging, I Universe, 2015)

Graph 2: The Effect of Well Known Vascular Inflammatory Free Radicals on Age and Inflammation

Graph 3: The Causes and Effects of the Three Stages of Chronic Interstitial Space Inflammation and the Capillary Cell Fail

Bibliography

First to my adult children, Tyler and Lily, for their love.

To Ryan Murphy, for creating all the illustrations.

To Kate, for her unwavering support and enthusiasm.

Introduction

Chronic inflammation is the dark energy in all interstitial spaces. Our poor lifestyle choices fuel it but we don’t expect its arrival. And when symptoms appear the fatigue and pain they cause are relentless. We can’t help but break down from the weight of the chronic inflammatory avalanche on our bodies and psyche. No end organ is spared as weight accumulates, and blood pressure, sugar and LDL cholesterol levels increase. In our busy and chaotic lives we don’t make the connection of these mid -life add-ons to chronic fatigue, achy knees, blurred vision, hearing loss, root canals, brain fog, or sleep deprivation. From combinations of denial, shock and stupor we are thrust into the medical industrial complex and the sudden volleys of replacement surgeries, stents, bypass grafts and the removal of sick and bloated gallbladders. Prescription medications proliferate to treat depression, anxiety, insomnia, pain, rheumatic diseases, hypertension, diabetes, and lipid disorders. We don’t like the way we feel or look but we accept our plight of chronic pain and fatigue. Meanwhile chronic inflammation is having a heyday in our interstitial spaces. By age 60, many of us have given up, content to find solace on the couch, curled up with a dog, bag of chips and a television or cell pho ne to keep

us company.

What becomes uncanny is how bad behavior feeds on itself. The couch and chips could lead to a long nap, a beer two or three or a bag of cookies. All of these choices are reactive, as they feed a chain reaction of addictions triggered by sugar and salt. The long daytime nap feeds nighttime insomnia, which will also trigger use of sleeping pills and midnight sugar snacking. Without a clue we have invited chronic inflammation into our interstitial spaces and it is bringing us to our knees with one poor choice after another. Before we can say helter -skelter, we are ensconced in disease treatment, surgeries and imaging studies. Everything gets harder, from thinking to getting out of a chair. Life suddenly seems unfair as odds and choices are stacked against us. And short of pills, more tests and surgeries, nobody seems to have a clue as to how to get out of this hole. We feel doomed and want comfort.

What we have to acknowledge is that most of what is offered by the medical establishment is stop-gap. We have to resist the tendency for a quick fix and realize the fix must come from our own choices. While drugs, imaging and surgery can be lifesaving and have their place, in the grand scheme of things, they mirror disease treatment and don’t solve the problem of disease prevention. In other words we never get to the point of stopping the chronic inflammatory train and getting off.

Yet that is exactly what we must do to get healthy. To become less reactionary and more intentional about how we live. This means no double talk about addictions, exercise, sleep, diet or how much stress we place ourselves under. Conscious choices should be made on the basis of do they increase or decrease inflammation. In most cases this becomes self- explanantory. When we base choice on outcomes, we have

transitioned from being reactionary to becoming intentional. Good things will happen. Suddenly wellness and prevention instead of disease treatment become passwords to our subliminal conscious.

Making matters worse, is that our health care providers may actually be antagonizing our efforts to change. As providers, we don’t get paid to spend time with patients to teach the right and wrong of lifestyle. Instead we get paid and rewarded for prescribing drugs for disease treatment and for timely referrals, procedures and injections to hunt for and treat more disease. Wellness and disease prevention are still mostly foreign concepts to the volume driven and employed primary care physician. As we open our prescription pads to treat disease we ignore the chronic inflammatory elephant in the room, which is stemming the disease we are treating.

The implication is that treating diseases is a late outcome of chronic inflammation (see graph 3 appendix). At the disease treatment stage, chronic inflammation has already capsized the interstitial space to its own liking. The capillary cells, which compose the smallest of blood vessels, have decomposed to the point where they no longer have capacity to control the trafficking whereabouts of immune arsenal entering or leaving interstitial spaces. This breakdown has produced an opportunity for chronic inflammation to birth. Over time and fueled with vascular inflammatory free radicals seeding into interstitial spaces, chronic inflammation harnesses its own set of alternative feedback loops provided by immune arsenal gone wrong. These loops displace those of the weakened capillary cell to create its own agenda, which is proinflammatory and anti-end organ. It is this maturing of chronic inflammation within the interstitial space that enables the proliferation of end organ disease venues that we as health care providers have learned so well to treat. Unbeknownst to both provider and patient is that without acknowledging prevention, we are losing the disease treatment battle. Meanwhile ever increasingly expensive technologies, drugs and surgeries weave their way into disease treatment in an ever increasing spiral of complexity. The trouble is that diseases adapt and always seem to be at least one step ahead of our prescription pads. The proliferation will be endless and will lead to bankrupting the medical establishment. I can’t tell which is worse, the greed from incentive induced providers, or from nervous patients, who want all the latest imaging and surgery in the hopes of finding the

silver bullet.

This is where wellness steps in. In this model, lifestyle adjustments block chronic interstitial space inflammation by reducing vascular inflammatory free radicals. Disease venues are prevented before they start. Or in some cases, with their fuel source exhausted, they dry up. Interstitial space feedback loop momentum shifts back to the capillary cell as they come out of hibernation and resume their pivot and swing dance. That is capillary cell outer membranes begin to once again choreograph immune arsenal trafficking into interstitial spaces, which increases the likelihood of successful interstitial space inflammatory breach removal, which then enables the swinging of mitochondrial combustion from energy to nitric oxide. Interstitial space wellness has made a comeback!

Pushing back against chronic inflammatory momentum is much easier to accomplish if attempted earlier in the game. By limiting the vascular inflammatory free radical fuel source much earlier, capillary cells don’t have to recover so much of their lost outer membrane receptors or mitochondrial volumes. The pace and how comprehensive the capillary cell recovery is will determine how well the interstitial space will revert back to optimal homeostasis.

Cutting off chronic interstitial space inflammatory fuel keys the capillary cell return of the pivot and swing dance. When they dance, not only breach elimination is more likely but it also unleashes the stemming and pacing of infrastructure refurbishment to itself and its allies as it nurtures end organ function. It does so through the reestablishment of its powerful feedback loop signaling system, involving its outer membranes and mitochondria, which previously had been disrupted by chronic inflammation.

The endothelial and capillary cell connection of looping their outer membrane permeability to either energy or nitric oxide mitochondrial combustion keys their pluripotent purpose of sanitizing the interstitial space and nurturing the end organ while also stemming refurbishment to itself and interstitial space allies. A robust capillary cell dance becomes the foundation for wellness; age reversal if you will.

There are at least three variables to the equation of eliminating vascular inflammatory free radicals within interstitial spaces. They are as follows:

The volume and diversity of free radical impingement.

The health of the endothelial and capillary cell.

The specificity and focus of arriving immune arsenal.

Any of these can lead to chronic inflammation but the one that affects the other two is free radical impingement. If vascular inflammatory free radical dispersion is overwhelming into the interstitial space it will cause capillaries to stop dancing and lead to a less competent immune arsenal entering the interstitial space. Trafficking goes into the mechanics of how vascular inflammatory free radicals block the capillary cell dance and disrupt feedback loop control of the interstitial to enable an increasingly rogue immune arsenal passage into the interstitial space. How immune arsenal are trafficked into the interstitial space makes or breaks who or what controls the space.

Tackling chronic inflammation early and head-on does not require a lot of out of pocket money but rather a different mindset about lifestyle choice. It is the day to day practice of making good choices that blocks chronic inflammatory influences, keeps capillary cells dancing and nurtures wellness. Adjustments may not be easy, especially when it comes from addictions to drugs, sugar and nicotine. Implied here is the right to fail, but also to try again with the added help of family, friends and colleagues. Not only does it take a village but also motivation to be reeducated and disciplined about good habits, reading labels, as well as reading between the lines. When it comes to food, what sugar and fat grams are labeled may not be what it seems.

When addictions cause life’s circumstances to go against us, it becomes easy to blame others. As victims we see our circumstances as being caused by outside influences. What is most important , if we are able to gain success over addictions, is that we take personal responsibility for them. Blaming others gives us ammunition to feel sorry for ourselves and continue the addiction.

Does chronic inflammation start with the expression from bad genes? Are we programed to fail? The accumulating evidence suggests that while our genes can make us more susceptible to alcohol or drug addiction, obesity, diabetes or elevated LDL cholesterol, lifestyle choices can trump these risks. If we adjust lifestyle early enough and stay at it, genetic risks don’t have to play out. By aborting proinflammatory behaviors we provide momentum to stream healthier choices that can overcome our genetic profiles. Lifestyle can frame wellness regardless of our genetic risks.

No one escapes death but we can have input into longevity and the quality of that life extension. Trafficking details the mechanics of how capillary cells manage immune competence and what that means in avoiding age and disease related baggage.

Robert L Buckingham, MD, FACP

CHAPTER 1

The Parable of the Farmer

In a far-away land lived a gifted corn farmer. From season his sweet corn tasted better than anyone else’s.

Each year, the farmer would change up the plant and sow slightly based on what he called prevailing conditions. This generally meant how cold the spring was and how much moisture remained in the soil after the winter thaw. He never let a fall pass without mulching and tilling and would let fields lay bare for a season. No two years were alike. Other farmers would try to emulate but their corn did not quite stack up.

One year, things changed-dramatically. Beetles darkened the sky from the south. Their wing flap could be heard for miles away as their sheer numbers in flight eclipsed the sun. Their intention was to eat anything green, which included corn.

Sensing the urgency to counter the beetles, the farmer amassed a team of specialists. Without much delay they presented their findings. Without swift intervention, nothing would be left of his corn crop.

At great expense large mesh nets were sown together and hoisted over some of the corn acreage. In another section, smelly manure was shoveled into the soil, and in still another cornfield, the immature stalks were drenched in water irrigation. The idea was to make the corn either less available or less appealing to the ravaged beetles.

The nets, manure, and water did not work. The beetles savaged the corn crop. Within a few days only barren corn stalks remained. There was finger pointing, but the cause of failure was clear. No one recommended killing the swarming beetles.

Without any crop and the farmer now penniless, he could only walk away from the farm.

Can you translate the parable?

The farmer represents a capillary cell, the soil, corn stalk and leaves the interstitial space, and the corn ear is the end organ. The beetle symbolizes the bombardment of vascular inflammatory free radicals. The netting, manure and water symbolize different types of immune arsenal meant to neutralize the free radicals. The consultants represent mesenchymal cells and the expense for their involvement is represented as capillary cell energy combustion.

Just as the horde of beetles destroyed the corn fruit, an overabundant and aggressive contingent of vascular inflammatory free radicals can bias chronic interstitial space inflammation and eventually destroy the end organ. In the parable, the mesh, manure and water are ineffective in limiting the beetle infestation. Within the interstitial space the inability to deliver enough of the right kind of immune arsenal will limit the capacity to eliminate inflammatory free radicals. Once the cash reserves are spent and the corn crop is ruined, the farmer can only away. Similarly, once the capillary mitochondria diminish in numbers to where they can no longer deliver energy to the capillary cell outer membranes, the capillary cell becomes incapable of interstitial space management and the end organ dies.

Could the outcome have been different? Yes, but the farmer would have had to change tactics and confront the beetle directly. The same is true with how capillary cells manage vascular inflammatory free radicals. In this case combining a lifestyle that diminishes the volume of free radicals penetrating the interstitial space coupled with the addition of the right kind of immune arsenal that would eliminate them should secure a different outcome.

CHAPTER 2

The Trap Door to Our Immune System

At the heart of interstitial space immune operations are the endothelia o f the vasculature system. Although all endothelia are codependent and contribute to optimal immune management, it is the capillary cell that facilitates the structured trafficking of immune arsenal combatants into interstitial spaces that secures an optimal working environment for end organs. What makes this job challenging is the volume and diversity of input that capillary cell outer membranes must integrate to enable effective interstitial space homeostasis. This becomes a constant moving target due to fluxes in end organ functional requirements, ever changing signals from other end organs, and the challenges of optimizing the interstitial space working environment. Even small missteps can chain react interstitial space compromise that will eventually limit capillary cell effectiveness and lead to a compromised end organ. At the heart of this compromise is the inability of capillary cells to deliver the right type or volume of immune arsenal into the interstitial space to maintain its sanitation. As sanitation deteriorates, end organ function declines. The end result is the tipping of the interstitial space towards chronic inflammation. When this happens, the space gets overrun by alternative sets of feedback loops from darker influences that divide the relationship between capillary and end organ cell. Nothing good comes from this divorce.

The remarkable part to the capillary cell’s evolution is how its outer membranes have coupled with mitochondria to affect a dual purpose. On the one hand increased outer membrane permeability and mitochondrial energy combustion increase immune trafficking into interstitial spaces to eliminate inflammatory breach. On the other hand, decreasing outer membrane permeability and swinging mitochondrial combustion to nitric oxide engineers restoration of its infrastructure, while increasing blood flow to enhance end organ functional capacity. In this manner changes in capillary cell outer membrane permeability coupled to mitochondrial combustion protects the interstitial space while also serving the end organ capacity to function. Capillary cell outer membrane permeability is tweaked based on what the end organ does and what kind of help it gets from interstitial space mesenchymal cells.

For decades after their discovery it has been thought that capillaries were passive cells that had no meaningful input in the management of the interstitial space. It was the end organ or the immune arsenal that did the regulating. Their purpose was to conduit gas exchange and energy substrate transfer to the end organ and enable immune arsenal entrance into the interstitial space when resourced by cytokines, white blood or mesenchymal cells.

This thinking has been turned inside out in the past two plus decades. Not only is the capillary cell far from a passive bystander, but a dynamic contributor to the interstitial space and end organ. Further, its success is linked to how well its outer membranes and mitochondria feedback loop each other, or how well they dance. This dance makes the interstitial space harmonize and the end organ sing. The pivot and swing melody reinforces optimal interstitial space sanitation and end organ function. It is connected to the quality assurance of ongoing capillary cell operations as well as to its allies-the mesenchymal cells and end organ itself. It turns out that the capillary cell is the head wagging the end organ tail.

It is the capillary cell dance rather than the end organ, mesenchymal cell or immune arsenal that enables the precise choreography of an immune response into the interstitial space to remove inflammatory breach and restore a sinewy interstitial space homeostasis. The effectiveness of this choreography in eliminating inflammatory breach determines how clean the interstitial space remains, which portends how well the space will support the capillary-end organ cell relationship. It also forms the basis for how well the capillary cell will dance. If the interstitial space is perpetually clouded with inflammatory debris, capillary cells don’t pivot and swing, as they get stuck in trying to eliminate this debris at the expense of their own restoration and end organ function. The persistence of interstitial space inflammatory debris blocks their dance. The imbalance cascades a host of capillary cell changes that render increasing dysfunction, which ties directly with associated declines in interstitial space hygiene and end organ ineptness. End organ disease venues, fatigue, pain and aging tag along. If inflammatory breach cannot be removed from the interstitial space, the capillary cell dance is blocked and this chain reacts the birthing of chronic inflammation. In this fashion capillary cells have become the gatekeepers of interstitial space homeostasis, the facilitators to the end organ function, and the stemming and pacing of rejuvenation to themselves and their mesenchymal and end organ cell allies.

The Capillary Cell Dance

The capacity for capillary cells to dual purpose is dependent on a robust pivot and swing dance based on feedback loop signaling exchanges between their outer membranes and mitochondria. Rigorous back and forth fluxing of outer membrane permeability means that capillary cells are busy receiving and sending myriads of different messages from a host of different contacts. It also means that they have been effective in trafficking immune arsenal into and out of their interstitial spaces to eliminate inflammatory breach and preserve its sanitation. It also implies that vascular inflammatory free radicals entering the interstitial space have been eliminated to enable the capillary outer membrane pivot of permeability. Finally it means that capillary cell mitochondria have been guided through feedback loop signaling from outer membranes to shift combustion from energy to nitric oxide. The capillary cell dance forms the basis for wellness as it implies the stalling out of chronic inflammatory influences.

The extent to which endothelia don’t pivot and swing, signals a capillary cell fail, and correlates with diminished mitochondrial volumes and outer membrane receptors. Chronic inflammation has established a permanent residence within the interstitial space and with it darker overtures to the fortunes of the end organ. Without the capillary cell dance, the interstitial space becomes a dark and foreboding place as the end organ becomes isolated and ineffective.

The Mitochondrial Combustion Swing

When capillary cell mitochondrial combustion swings to nitric oxide, three critically important adjustments occur to the capillary cell. First, within mitochondria, nitric oxide combustion shifts acetyl coenzyme A away from the energy producing cytochromes and Krebs cycle and instead is mobilized outside of the mitochondria towards ribosomes and rough endoplasmic reticulum. The shift in acetyl coenzyme A (acetyl CoA) signals initiation of protein synthesis to replace worn out infrastructure. The shuttling of acetyl coenzyme A towards ribosomes in the cytoplasm is a necessary transition for capillary cell renewal and future quality assurance; in essence a prerequisite to disease prevention and anti-aging. When acetyl coenzyme A migrates to ribosomes and rough endoplasmic reticulum it provides a usable energy substrate for protein synthesis. With uneven, insufficient or blocked nitric oxide combustion, acetyl CoA mobilization is ineffective thereby cascading protein replacement mistakes or inadequate protein repair.

Second, when mitochondrial combustion swings away from energy combustion, the outer membranes no longer require ATP for active transport of immune arsenal. The unused and accumulating cytoplasmic ATP, along with calcium ions, becomes an important signaling loop that feeds back to the mitochondrial matrix to halt energy combustion and activate the enzyme nitric oxide synthase (NOS). NOS, not only increases nitric oxide production, but feeds back to the mitochondrial inner membrane cytochromes to inhibit the transfer of electrons. This serves as further impetus to block mitochondrial energy production. In this manner nitric oxide synthase facilitates nitric oxide production while simultaneously switching off energy combustion.

Third, nitric oxide (NO) combustion results in the production of a diffusible gas. This gas can easily diffuse out of the mitochondria to activate protein synthesis, initiate replication and relax downstream arteriole smooth muscle to increase blood flow towards the affected capillary cell and its end organ partner. More blood flow means more oxygen and nutrient delivery to the capillary bed which in turn is transferred directly to the end organ. More oxygen and nutrient to the end organ translates into improved potential to function and implies that their mitochondria can rev energy combustion. As capillary mitochondria shift to nitric oxide combustion, end organ mitochondria alternatively shift to energy combustion to improve performance. When capillaries are dealing with interstitial space inflammatory debris, they shift to energy combustion and their end organ mitochondrial partners to nitric oxide production. The persistence of combustion in any one direction will eventually doom both the capillary and end organ cell due to the buildup of toxic free radical exhaust (superoxide or hydroxynitriles) from a one- sided combustion.

By blocking immune arsenal movement into the interstitial space, increasing blood flow to augment end organ function, stemming the refurbishment of its infrastructure and interstitial space allies, while diversifying combustion exhaust, capillary cell mitochondrial nitric oxide combustion keys capillary cell quality assurance and execution of optimal end organ function. The conversion to nitric oxide combustion does not happen unless capillary cell outer membrane permeability can downshift. The downshift is made possible by making the removal of vascular inflammatory free radicals and other inflammatory debris within the interstitial space as easy as possible. Lifestyle, lifestyle, lifestyle.

The inability to remove inflammatory breach within the interstitial space becomes the lynchpin of the capillary cell dance. In simple terms it becomes dependent on vascular inflammatory free radical impingement. In other words the fluxing pivot and swing capillary cell dance becomes the key facilitator to blocking